Vonvendi

VONVENDI is a purified recombinant von Willebrand factor (rVWF) expressed in Chinese Hamster Ovary (CHO) cells. VONVENDI is produced and formulated without the addition of any exogenous raw materials of human or animal origin in the cell culture, purification, or formulation of the final product. The only proteins present in the final container product other than rVWF are trace quantities of mouse immunoglobulin (IgG, from the immunoaffinity purification), host cell (i.e., CHO) protein, rFurin (used to further process rVWF), and recombinant factor VIII (rFVIII).

Von Willebrand factor is a large multimeric glycoprotein that is normally found in plasma, and stored as ultra-large multimers in alpha-granules of platelets and intracellular organelles known as Weibel-Palade bodies, prior to secretion into the blood.1 Once the VWF is released to the blood stream and in contact with ADAMTS13 a (proteolytic enzyme in blood), it is cleaved to smaller sizes that can be detected with SDS agarose gels as multimer bands, representing the various species of VWF within the circulation. VONVENDI is rVWF that contains ultra-large multimers in addition to all of the multimers found in plasma as it is not exposed to proteolysis by ADAMTS13 during the manufacturing process.

VONVENDI is formulated as a sterile, non-pyrogenic, white to off-white powder for intravenous injection after reconstitution. VONVENDI in a single-use vial contains nominally 650 or 1300 International Units (IU) VWF Ristocetin Cofactor (VWF:RCo). The product contains the following stabilizers and excipients: tri-sodium citrate-dihydrate, glycine, mannitol, trehalose-dihydrate, and polysorbate 80.

The product contains no preservative. When reconstituted with the provided sterile water for injection the final solution contains the following stabilizers and excipients in targeted amounts:

Table 3 : Concentration of Stabilizer and Excipient after Reconstitution

Each vial of VONVENDI is labeled with the specific number of units of VWF: RCo expressed in international units (IU), which are based on the current World Health Organization (WHO) standard for VWF concentrate. After reconstitution of the lyophilized powder and filtration/withdrawal into a syringe, all dosage strengths yield a clear, colorless solution free of particles.

VONVENDI [von Willebrand factor (Recombinant)] is a recombinant von Willebrand factor indicated for on-demand treatment and control of bleeding episodes in adults (age 18 and older) diagnosed with von Willebrand disease.

No drug interactions have been reported by the manufacturer. However, you should tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Not all drug interactions are known or reported and new drug interactions are continually being reported.

Serious side effects have been reported with Vonvendi including the following:

Blood Clots. Vonvendi may increase your risk of developing a blood clot, which could lead to pulmonary embolism (a clot in your lungs), stroke, or heart attack. Alert your doctor immediately if you have any of the following signs or symptoms:

• pain or swelling in your legs
• discoloration
• trouble breathing
• shortness of breath
• cough
• coughing up blood
• feeling faint or lightheaded
• chest pain
• discomfort in arms, shoulder, neck, or back
• nausea or vomiting
• numbness or weakness in the face, arm, or leg (especially on one side of the body)
• confusion
• trouble speaking
• dizziness
• severe headache

Hypersensitivity Reactions. Severe allergic reactions may occur with Vonvendi. Tell your healthcare provider about any signs or symptoms of hypersensitivity, which include the following:

• chest pain
• swelling of the face, eyes, lips, tongue, arms, or legs
• difficulty breathing or swallowing
• rash

Neutralizing Antibodies. Your body can make neutralizing antibodies which inhibit von Willebrand factor and/or factor VIII from working correctly. Your doctor will perform blood tests to check your von Willebrand factor activity and the presence of any inhibitors. If high levels of inhibitors are detected, Vonvendi may not work for you.

Laboratory Monitoring. In addition to checking for neutralizing antibodies, your doctor will also check your von Willebrand factor levels to make sure they are not too high, which could increase your risk of blood clots.

Do not take Vonvendi if you are allergic to Vonvendi or to any of its ingredients, or are allergic to mice or hamsters.

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Vonvendi, there are no specific foods that you must exclude from your diet when receiving this medication.

Tell your doctor if you are pregnant or plan to become pregnant.

No studies have been done in pregnant women or animals with Vonvendi, therefore it is unknown if Vonvendi can be harmful to an unborn baby or affect a woman's ability to become pregnant. Vonvendi should be given to pregnant women only if clearly needed.

• Store Vonvendi in the original box and keep away from light.
• Store Vonvendi in the refrigerator 2°C to 8°C (36°F to 46°F) or store at room temperature up to 30°C (86°F) for up to 12 months. Do not freeze.

If you store it at room temperature:

• Write the date it is taken out of the refrigerator on the box
• Do not put it back in the refrigerator
• Do not use after 12 months from the date noted on the box or after the expiration date.

Storing the mixed (reconstituted) product:

• After mixing dry product with supplied sterile water, store the product at room temperature not to exceed 27 °C (81°F) for up to three hours. Discard after 3 hours. 

Keep this and all medicines out of the reach of children.

Keep all appointments with your doctor and the laboratory.

Von Willebrand factor is injected into a vein through an IV. You may be shown how to use an IV at home. Do not give yourself this medicine if you do not understand how to use the injection and properly dispose of needles, IV tubing, and other items used.

Read all patient information, medication guides, and instruction sheets provided to you. Ask your doctor or pharmacist if you have any questions.

Von Willebrand factor is a powder medicine that must be mixed with a liquid (diluent) before using it. If you are using the injections at home, be sure you understand how to properly mix and store the medicine. Mixed medicine must be used within 3 hours if you keep it at room temperature.

Do not shake the mixed medicine. Prepare your dose only when you are ready to give an injection.

Do not use the medicine if it looks cloudy or has particles in it. Call your pharmacist for new medicine.

Tell your doctor if you have any changes in weight. Von Willebrand factor doses are based on weight, and any changes may affect the dose.

You may need frequent medical tests to help your doctor determine how long to treat you with von Willebrand factor.

Use a disposable needle and syringe only once. Follow any state or local laws about throwing away used needles and syringes. Use a puncture-proof "sharps" disposal container (ask your pharmacist where to get one and how to throw it away). Keep this container out of the reach of children and pets.

Store this medicine in its original carton in a refrigerator until you are ready to prepare your dose. Do not allow the to medicine freeze.

You may also store the carton at room temperature for up to 12 months.

Do not use this medicine if the expiration date on the label has passed.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Since von Willebrand factor is used when needed, it does not have a daily dosing schedule. Call your doctor promptly if your symptoms do not improve after using von Willebrand factor.

Contraindications

Do not use in patients who have had life-threatening hypersensitivity reactions to von Willebrand factor (recombinant) or its components (mannitol, trehalose, sodium chloride, histidine, Tris, calcium chloride, polysorbate 80, and hamster or mouse proteins).1

Warnings/Precautions

Thromboembolic Reactions

Thromboembolic reactions, including disseminated intravascular coagulation (DIC), venous thrombosis, pulmonary embolism, myocardial infarction, and stroke, can occur, particularly in patients with known risk factors for thrombosis. Monitor for early signs and symptoms of thrombosis such as pain, swelling, discoloration, dyspnea, cough, hemoptysis, and syncope.1

In patients requiring frequent doses of von Willebrand factor (recombinant) with recombinant factor VIII, monitor plasma levels for FVIII:C activity because an excessive rise in factor VIII levels can increase the risk of thromboembolic complications.1

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, may occur. Symptoms can include anaphylactic shock, generalized urticaria, angioedema, chest tightness, hypotension, shock, lethargy, nausea, vomiting, paresthesia, pruritus, restlessness, wheezing, and/or acute respiratory distress. If signs and symptoms of severe allergic reactions occur, immediately discontinue administration of von Willebrand factor (recombinant) and provide appropriate supportive care.1

Von Willebrand factor (recombinant) contains trace amounts of mouse immunoglobulin G (MuIgG) and hamster proteins less than or equal to 2 ng/IU von Willebrand factor (recombinant). Patients treated with this product may develop hypersensitivity reactions to non-human mammalian proteins.1

Neutralizing Antibodies

Neutralizing antibodies (inhibitors) to von Willebrand factor and/or factor VIII can occur. If the expected plasma levels of VWF activity (VWF:RCo) are not attained, perform an appropriate assay to determine if anti-VWF or anti-FVIII inhibitors are present. Consider other therapeutic options and direct the patient to a physician with experience in the care of either von Willebrand disease or hemophilia A. 1

In patients with high levels of inhibitors to VWF or factor VIII, von Willebrand factor (recombinant) therapy may not be effective and infusion of this protein may lead to severe hypersensitivity reactions. Since inhibitor antibodies can occur concomitantly with anaphylactic reactions, evaluate patients experiencing an anaphylactic reaction for the presence of inhibitors.1

Monitoring Laboratory Tests

• Monitor plasma levels of VWF:RCo and factor VIII activities in patients receiving von Willebrand factor (recombinant) to avoid sustained excessive von Willebrand factor and/or factor VIII activity levels, which may increase the risk of thrombotic events, particularly in patients with known clinical or laboratory risk factors.1

• Monitor for development of von Willebrand factor and/or factor VIII inhibitors when suspected. Perform appropriate inhibitor assays to determine if von Willebrand factor and/or factor VIII inhibitors are present if bleeding is not controlled with the expected dose of von Willebrand factor (recombinant).1

Specific Populations

There are no studies of von Willebrand factor (recombinant) use in pregnant women. The background risk of major birth defects and miscarriage in the indicated population is unknown; however, the background risk of major birth defects in the U.S. general population is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. Animal reproduction studies have not been conducted with von Willebrand factor (recombinant). It is not known whether von Willebrand factor (recombinant) can cause fetal harm when administered to a pregnant woman or whether it can affect reproduction capacity. Von Willebrand factor (recombinant) should be given to a pregnant woman only if clearly needed.1

There is no information regarding the presence of von Willebrand factor (recombinant) in human milk, its effects on the breastfed infant, or its effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for von Willebrand factor (recombinant) and any potential adverse effects on the breastfed infant from von Willebrand factor (recombinant) or from the underlying maternal condition.1

Safety and effectiveness in pediatric patients below the age of 18 years have not been established.1

Clinical trials of von Willebrand factor (recombinant) did not include subjects aged 65 and over to determine whether they respond differently compared to younger subjects.1

Common Adverse Effects

The most common adverse reaction observed (≥2% of subjects) was generalized pruritus.1

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if you have any side effects that bother you or do not go away.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.